Diazo-ketones for synthesizing steroids



United States Patent 0 DIAZO-KETONES FOR SYNTHESIZING STEROIDS Martin W.Farrar, Webster Groves, Harold Rnifelson, St.

Louis, and William S. Knowles, Kirkwood, M0., assign'ors to MonsantoChemical Company, St. Louis, M0 a corporation of Delaware No Drawing.Original application July 23, 1953, Serial No. 369,944, now Patent No.2,759,929, dated August 21, 1956. Divided and this application June 21,1956, Serial No. 592,761

1 Claim. (Cl. 260-23955) This invention relates to methods and novelcompounds of the cyclopentanodimethylpolyhydrophenanthrene series havinga 3-keto group and a double bond in the 4,5 position, which compoundsare intermediates in proceeding from a 17 formyl cyclopent 16eno-10,13-dimethyl- A -decahydrophenanthren-3-one to a17-('acyloxyacetyl) 17 hydroxy cyclopentano 10,13-dimethyl-Adodecahydrophenanthren-3,1l-dione. In particular this invention relatesto methods and novel compounds useful in the preparation of acylderivatives of 3,11,20-tn'ketol7,2l-dihydroxy-A -pregnene from a3-keto-17-formyl- A -androstatriene.

CHO

CHsOR I If an acyl halide forming agent, (4) reacting the resultantacidhalide with diazomethan, (5) reacting the thawketone so formed with acarboxylic acid to form a 17-(acyloxyacetyl)-16,17-oxido-cyc1opentano-10,13-dimethyl- A-decahydrophenanthren-3-one, (6) reacting said latter compound with ahydrogen halide, (7) reacting the 16 halol7-hydroxy-17-(acy1oxyacety1)-cyclopentano-- 10,13 dimethyl A-decahydrophenanthren-3-one so formed with a hypohalous acid, (8)oxidizing the 9,16- dihalo-l 1,17-dihydroxy-17-(acyloxyacetyl)-cyclopentano- 10,13 -'dimethyl A -dodecahydrophenanthren-3-one with acomplex of chromium oxide and a tertiary amine, (9) de-halogenating the9,16-diha1017-hydroxy-17-(acyloxyacetyl) cyclopentano 10,13-dimcthyl-A-dodecahydrophenanthren-3,11-dione so as to produce a l7-(acyloxyacetyl)17 hydroxy-cyclopentano-10,13-dimethyl-A-dodecahydrophenanthren-3,1l-dione. The aforesaid sequence of steps isoutlined schematically as follows:

0H0 COOH I I I l n III OHN: =0 00X '3 I I I O l 0- 0- V IV OHiOR CHgOR=0 -,0 OH HO Hal Hal VIII CHaOR This invention will be described indetail with respect to its preferred embodiment but it is to beunderstood that suchis not limitative of this invention.

The first step in the process of this invention is the epoxidation of al7-formyl-cyclopent-l6-eno-l0,l3 dimethyl-A -decahydrophenanthrena3-oneto a 16,17- oxido l7 formyl cyclopentaho-IO,l3-dimethyl-Adecahydrophenanthren-3-one (Compound 11) employing an oxygen furnishingagent such as the organic per-acids or hydrogen peroxide in an amountcorresponding to approximately one chemical equivalent. The epoxidationis ordinarily carried out by mixing the oxidant and the 17formyl-cyclopent-l6-eno-10,l3dimethyl-A -decahydrophenanthren-3-onetogether in an organic medium which is non-reactive under the reactionconditions. Suitable media include chloroform, carbon tetrachloride,diethyl ether, glacial acetic acid, methanol, ethanol, isopropanol, andthe like. The temperature employed in the epoxidation may vary widelybut ordinarily will be in the range of from about 10 C. to about 50 C. Aconvenient reaction medium when the oxidant is hydrogen peroxide is alow molecular weight alcohol.

As illustrative of the first step of the process of this invention isthe following:

Example I To a suitable reaction vessel containing 50 parts by weight(substantially 0.169 mol) of dl-3-keto-l7-formyl- N -androstatriene (M.P. l78l78.5 C.) dissolved in 4200 parts by weight of methanol maintainedat about 5 C. is added approximately 170 parts by weight of sodiumcarbonate as a 5% aqueous solution followed by a methanol-hydrogenperoxide mix containing approximately 5.7 parts by weight of hydrogenperoxide. mix so obtained is stirred for about 16 hours at about C.Thereupon substantially all of the methanol is removed by vacuumdistillation and the residue is then taken up with chloroform. Thechloroform solution is then washed with Water and dried over anhydrousmagnesiurn sulfate. Upon evaporation of the chloroform there is obtaineda white solid residue, which upon triturating with diethyl ether yieldswhite crystalline dl-3- keto-16,17-oxido-l7-formyl-A -androstadiene.

Similarly the individual optically active isomers such as the naturalmodification of 3-keto-l6,l7-oxido-17- formyl-A -androstadiene areobtained beginning with the appropriate optically active isomer of3-keto-l7- formyl- -androstatriene. Thenatural modification of3-keto-l6,l7-oxido-17-formyl-A -androstadiene is obtained employing theprocedure of Example I but replacing dl-3-keto-17-formyl-A-androstatriene with the dextro-rotatory form of 3-keto-l7-formyl-Aandrostatriene (melting point 1605-1615 C.).

The next step in the process of this invention is the conversion of theformyl gro'upfi. e. the substituent in the l7-position, to a car boxygroup (Compound III of the schematic diagram). This is readily broughtabout employing a mild oxidizing agent such as silver oxide, sodiumchromate in acetic acid, and the like. As illus The trative of thepreparation of a 3-keto-l6,17-bxido-l7-carboxy-A -androstadiene is thefollowing:

Example II To an intimate 'mixture containing approximately 200 parts byweight of diox'ane, approximately 192parts by Weight of 2.74 N sodiumhydroxide, and approximately 44.6 parts by weight of silver nitrate isslowly added approximately 40 parts by weight ofdl-3-keto-l6,17-oxidol7-formyl-a' -androstadiene. Upon completion of theaddition of the ,16,l7-oxido compound approximately 200 parts by weightof water and approximately 200 parts by weight of dioxane is added withconstant agitation. Thereafter the mix is agitated for about one hourand is then filtered. The collected residue is washed with water and thewashings combined with the original filtrate. The aqueous layer isacidified andth'en extracted with chloroform. The chloroform extractsare combined, dried and subjected to vacuum distillation. Uponevaporation of the chloroform there is obtained 'a solid residue whichupon triturating with diethyl ether yields 35 parts by weight ofcrystalline dl-3-keto-16,17-oxido-17-carboxy- A androstadiene.

Similarly the individual optically active isomers such as the naturalmodification of 3-keto-16,17-oxido-l7-carboxy-A -androstadiene areobtained beginning with the appropriate optically active isomer of3-keto-16,l7- oxido-17-formyl-A -androstadiene.

The next step in the process of this invention the carboxylic acid(Compound III) is converted to its acid halide (Compound IV) employingan acyl halide forming agent such as oxalyl chloride and the like. Asillustrative of the preparation of the acid halide (Compound IV) is thefollowing:

Example III To a solution containing approximately parts by weight ofdI-3-keto-l6,l7-0xido-17-carboxy-A -androstadiene in approximately 4000parts by Weight of anhydrous methanol is added suflicient sodiummethylate to neutralize the epoxy acid. The methanol is removed byvacuum distillation and to the residue is added and intimately mixedabout 450 parts by weight of benzene and about 2.5 parts by weight ofpyridine followed by about 250 parts by Weight of oxalyl chloride whilemaintaining the temperature at about 10 C. The mix so obtained isallowed to stand for about 30 minutes, whereupon the mix is subjected tovacuum distillation while maintaining the temperature at about 15 C. Theresidue is then taken up with about 500 parts by weight of benzene andagain subjected to vacuum distillation at about 15 C. The residueistaken up with about 250 parts by weight of benzene and filtered. Uponsubjecting the filtrate to vacuum distillation there is obtained thesolid acid chloride of dl-3-keto-l6,17-oxido-l7 carboxy-A--androstadiene.

Similarly the individual optically active isomers such as the acidchloride of the natural modification of 3-keto- 16,l7oxidol7-carboxy-A-androstadiene are obtained from the appropriate optically activeisomer.

The next step in the process of this invention is the preparation of thediazoketone (Compound V) by reacting diazomethane with an acid halide ofa 16,17-oxido- 17 carboxy-cyclopentano-10,13-dimethyl-A-decahydrophenanthren-3-one. Ordinarily an excess of two chemicalequivalents of diazomethane is employed in converting the acid halide(Compound IV) to the diazoketone (Compound V) and in general the processis carried out in an inert organic solvent such as diethyl ether,benzene, dioxane, toluene, etc., at temperature in the range of 20 to 40C. As illustrative of the preparation of the diazoltetone is thefollowing:

Example IV To a suitable reaction vessel containing an ether solutioncontaining 100 parts by weight of diazomethane is added approximately 50parts by weight of the acid chloride ofdl-3-keto-16,17-oxido-17-carboxy-A -androstadiene dissolved in 500 partsby weight of benzene while maintaining the temperature at about 0 C. Themixture so obtained is then agitated for about one hour at about 0 C.The mix is then subjected to vacuum distillation to remove the solventswhereupon there is obtained 'yellow crystallinedl-3,20-diketo-16,17-oxido-21- diazo-A -pregnadiene.

Similarly the individual optically active isomers such as the naturalmodification of 3,20-diketo-16,17-oxido-2ldiazo-A -pregnadiene areobtained beginning with the acid halide of the appropriate opticallyactive isomer of 3-keto-16,l7-oxido-17-carboxy-A -androstadiene.

' The next step in the process of this invention is the formation of the17-(acyloxyacetyl)-16,17-oxido-cyclopentano 10,13-dimethyl-A-decahydrophenanthren-3- one (Compound VI) from the diazoketone(Compound 'V) by heating the latter in the presence of a monocarboxylicacid such as acetic acid, propionic acid, butyric acid, valeric acid,caproic acid, lauric acid, stearic acid, phenylacetic acid,S-phenylpropionic acid, benzoic acid, toluic acid, etc., in the presencewhere desirable of an inert organic solvent such as benzene, toluene,xylene, dioxane, etc. It is preferred that the carboxylic acid be afatty acid and preferably one containing from 2 to 4 carbon atoms. Asillustrative of this step is the following:

Example V To a suitable reaction vessel containing approximately 5000parts by weight of acetic acid is added approximately 50 parts by weightof dl-3,20-diketo-16,17-oxido-21-diazo- A -pregnadiene and the mix soobtained heated at about 90-95 C. for about 30 minutes. The resultantmix is then subjected to vacuum distillation and the residue so obtainedtaken up with chloroform. The chloroform solution is then washed withaqueous sodium bicarbonate, then with water and finally dried. Uponremoval of the solvent there is obtained soliddZ-3,20-diketo-l6,17-oxido- 21-acetyloxy-A -pregnadiene in the form ofwhite crystals.

Similarly the individual optically active isomers such as the naturalmodification of 3,20-diketo-16,17-oxido-21- acetyloxy-A -pregnadiene areobtained from the appropriate optically active isomer of3,20-diketo-l6,l7- oxide-21diam-A -pregnadiene.

The next step of the process of this invention is the opening of theepoxide grouping by reacting the 17- (acyloxy acetyl) 16,17 oxidocyclopentano 10,13- dimethyl A4901) decahydrophenanthren 3 one (CompoundVI) with a hydrogen halide such as HCl, HBr or HI which results in theformation of a halohydrin (Compound VII), namely16-halo-17-hydroxy17-(acyloxyacetyl) cyclopentano 10,13 dimethyl Adecahydrophenanthren-3-one. This reaction is preferably carried out inan inert organic solvent containing dissolved therein the hydrogenhalide reactant and at a temperature in the range of about -20 C. toabout 40 C. As illustrative of this step is the following:

Example VI "Approximately 40 parts by weight of dl-3,20-diketo- 16,17oxido 21 acetyloxy M pregnadiene is admixed with aproximately 3000 partsby weight of acetic acid and approximately 1000 parts by weight ofbenzene in a suitable reaction vessel. Thereto is added whilemaintaining the temperature at about 0 C. approximately parts by weightof a 38% acetic acid solution of hydrogen bromide and the mix soobtained agitated for about 30 minutes at about 0 C. To the mix is thenadded an equal volume of water and the composite so obtained extractedwith several small portions of chloroform. The chloroform extracts arecombined, washed with water and dried over anhydrous magnesium sulfate.Upon subjecting the so dried solution to vacuum distillation in order toremove the chloroform there is obtained white crystalline dl 3,20 diketo16p bromo 17a hydroxy- 21acetyloxy-A ?-pregnadiene.

In a similar fashion but employing hydrogen chloride instead of hydrogenbromide white crystalline dl-3,20- diketo 16B chloro 17a hydroxy 21acetyloxyd -pregnadiene is obtained from dl-3,20-diketo-l6,17- ox-ido-21acetyloxy-A -pregnadiene.

Similarly the individual optically active isomers such as the naturalmodification of 3,20-diketo-16B-bromo- 17u-hydroxy-21acetyloxy-A-pregnadiene are obtained from the appropriate optically active isomerof 3,20 diketo 16,17 oxido 21 acetyloxy (3 pregnadiene.

The next step in the process of this invention is the reacting of the16-halo-17-hydroxy compound Compound VII) with a hypohalous acid to formthe 9,16-dihalo-11-17- dihydroxy 17 (acyloxyacetyl) cyclopentano 10,13-dimethyl A dodecahydrophenanthren 3 one (Compound VIII). The additionreaction is brought about by mixing a solution of a hypohalous acid,preferably hypobromous acid, with a solution of a 16-ha1o-17-hydroxy- 17(acyloxyacetyl) cyclopentano 10,13 dimethyl- A-decahydrophenanthren-3-one at a temperature in the range of about 0 to30 C. The 9-halo and ll-hydroxy substituents so introduced bear a transrelationship to one another, that is one occupies the plane above ring Cwhile the other occupies the plane below ring C, however, it is to beunderstood that the element of this invention is-not limited to anyassumption as to chemical structure but pertains broadly to the9-halo-11-hydroxy addition product of a hypohalous acid and a16-halo-17- hydroxy 17 (acyloxyacetyl) cyclopentano 10,13- dimethyl Adecahydrophenanthren 3 one (Compound VII). Various solvents which areinert under conditions of the addition reaction may be used in thepreparation of the 9-halo-11-hydroxy addition product (Compound VIII),for example, acetone, methyl ethyl ketone, methyl acetate, ethylacetate, tert. butanol, etc.

In this step of the process of this invention it is preferred that thehypohalous acid employed be hypobromous acid and such can be prepared inseveral ways, for example by mixing mercuric oxide with bromine andwater and filtering off the mercuric bromide thus formed, or by mixingN-bromoacetamide with waterand tertiary butanol or, preferably, bymixing a solution of N-bromosuccinimide l /NBr in a suitable inertorganic solvent, e. g. acetone, tertiary cyclopentano 10,13 dimethyl-.37 A -decahydrophenanthren-3-one (Compound VII) or, preferably, thehypobromous acid is prepared in the presence of the reactant (i.'e.Compound VII) so that the elements of hypobromous acid add to'the 9-11double bond as soon as they are formed. As illustrative of this step ofthe process of this invention employing hypobromous acid is thefollowing:

Example VII To anagitatingsolution containing substantially 63 parts byweight of dl-3,20-diketo-16fl-bromo-17u-hydroxy 21 acetyloxy -"Apregnadiene, substantially 2800 parts by Weight of'a'cetone andsubstantially 1200parts by Weight of water is added at about'Q-S" C.approximately .50 parts by weight of 1N sulfuric acid. To them cooledand acidified solution is slowly added a solution'containingsubstantially 35 parts by weight of N bromo-succinimide in approximately.360 parts -oy weight of acetone. Upon completion of the N-bromosuccininiide addition .the'rnix is agitated for about 5 hours at'a'bout0+5 (3., the bromo-hy'd'rin crystallizes from the solution duringtheagitation. At the end of the agitation period aqueous sodium sulfiteisadded to destroy the excess .N brommsuccinimide andthen the mix isneutralized with sodium bicarbonate. The mix is then filtered and theresiduewashed first with Water, then with acetone and dried. The whitecrystalline product so obtained is dl 3,20 -'dileto '91:,175 dibromo1118,1701- dihydroxy-Zl-acetyloxy-a' -pregnene.

In a similar fashion beginning with dl 3,20-diketo- 16 8 'chloro 17ahydroxy 21 acetyloxy A pregnadiene White crystallinedl-3,20-diketo-9u-bromo- 16,3 "chloro 116,17a -dihydroxy -"21'acetyloxy- M-preghene is obtained.

all 3,20 diketo 9:1,165 dichloro 'lldl'lm dihydroxy-Z1=acetyloxy-A-pregnene may be prepared by admixing the 9ot-bromo-l15-hydroxy compound(i. e. the product of Example VII) with a small amount of potassiumacetate and boiling the mix in alcohol to effect formation 'ofthe 9 11,16-17'dioxido'derivative, the dioxido compound so obtained uponreacting with hydrochloric acid in chloroform at about 0-5 "C. yieldstil-'3, 20 diketo 90,l'6fi dichloro ll';8,l7a dihydroxy-ZI-acetyIoXy-M-pregnene.

Similarly the individual optically active isomers of 3,20 diketo 904,165'dihalo 115,170: dihydroxy- 21-acetyloxy d pregnene, e. g.'the naturalmodification of 3,20 diketo -"9u,'16;8 dibrorno -.11fl,17adihydroxy-2l-acetyloxy u pregnene are obtained from the appropriateoptically active 3,20-diketo-16fl-halo-17a-hydroxy-21=acetyloxy=Apregnadiene.

The next stcpin the process of this invention is the oxidation 'of'the'l'l-hydroxy substitue'nt of Compound VIII of the foregoing schematicdiagram to produce the 16-halo -17-hydroxy-"17-(acyloxyace1tyl)-cyclopentano-9- halo-10,1'3 dimethy1 Aidode'cahydrophenanthren-3,1 1- dione (Compound IX) where x is a halogenatom'sucn as bromine, chlorine and iodine and where R is an acyl radicalderived from a hydrocarbon monocarb'oxylic acid. This oxidation step isbrought about'in an anhydrous system .by mixing a complex of'chromiumoxide and a tertiary amine, such as pyridine or the variouspicolines, etc, withthe -9-ha1oll-hydroxy compound (Compound VHI). Asillustrative of this'step of the process of this invention is thefollowing:

Example VIII To an agitated complex of chromium trioxide and pyridineprepared in the cold by admixing 50 parts by weight of chromium trioxidewith 500 parts by weight of pyridine is added substantially 50 parts byweight of di-3, 20- diketo 9,16 dibromo 115,111 dihydroxy-21-acetyloxy-.l*-pregnenc in approximately 800 parts by weight of pyridinewhile maintaining the temperature at about 10 C. The mixture so obtainedis permitted to stand at room temperature for about 16 hours withoccasional agitation. The mixture is then filtered and the residuewashed with pyridine. The pyridine wash and the original filtrate arecombined and the solution so formed is poured into five times its weightof water and the composite extracted with chloroform. The extracts arecombined and cooled to about 0 C. The cooled solution is then washedwith dilute hydrochloric acid and then with water. The organic layer isrecovered, dried, and evaporated to dryness. The residue is whitecrystalline dl 3,11,20 trilreto 90c,l6fl-dibromo-17a-hydroxy-Z1-acetyloxy-a -pregnene.

Replacing (ll-3,2Q-dilietO-9oc,16,8-dlb10n10-l1fi,17a-dihydroxy-2lracetyloxy-A -pregnene in Example VIII with an equalWeight of dl-3,20-diketo-9a,16fi-dichloro-l1317adihydroxy-21-acetyloxy-A-pregnene and subjecting same to the series of steps set forth inExample VIII ail-3,11,20-

tI'lkEIO-9C4,l6,3-dl0hl0l0 17cc hydroxy 2lacetyloxy-A pregnene isobtained.

In a similar fashion the individual optically active isomers of3,11,20-triketo-9a,l6;3-dihalo-l7a-hydroxy-2lacetyloxy-A -pregnene, e.g. the natural modification of 3,11,20 trilceto9e,16,8-dibromo-l'7u-hydroxy-21-acetyloxyA -pregnene is obtained fromthe appropriate optically active 3,20-diketo 90:,163 dihalo-llfl,17u-dihydroxy-Z 1-acet ,loxy-A pregnene.

The next step in the process of this invention is the removal of the9-halogen and l6-halogen substituents on the 16-halo17-hydroxy-17-(acyloxyacetyl)-cyclopentano-9-halo-l0,l3-dimethyl Adodecahydrophenanthren- 3,11-dione. In this step the halogen substituentin the 9-position is removed first to provide a 16-ha1o-17-hydroxy-l7-(acyloxyacetyl)-cyclopentano-10,1S-dimethyld-dodecahydrophenanthren-3,1l-dione (Compound X) which compound upondehalogenating produces a 17- hydroxy-17-(a cyloxyacetyl-cyclopentano-10, l 3-dimethyl- X dodecahydrophenanthren-S,1l-dione(Compound XI). It is preferred to remove both halogen substitueuts inone operation and as illustrative of this employinga large excess ofRaney nickel is the following:

Example IX To a suitable reaction vessel containing 20 parts by weightof Raney nickel, approximately 200 parts by Weight of acetone and about20 parts by weight of'water is added approximately 3.5 parts by weightof ail-3,11,20-

pregnene and the mixture so obtained refluxed in an atmosphere ofnitrogen for about 4 hours. The reaction mix is then filtered and theresidue washed with warm acetone. The-washings and original filtrate arecombined and subjected to vacuum distillation. The residue is then takenup with chloroform and the solution so formed washed withwaterand dried.The dried solutionisthen subjected to vacuum distillation'whereuponthere is-obtained white crystalline ell-3,11,20-triketo-1hhydroxy-Zlacetyloxyeo -pregnene-(M. P. 240-243" C.) which compound is identicalwith'the acetate of racemic (dl) cortisone.

Similarly the individual optically active isomers such as the .naturalmodification (dextro-rotatory form) of3,11,2O-trikcto-l7rx-hydroxy-2l-acetyloxy-A*-pregnene are 9 obtainedbeginning with the approximate optically active isomers of3,11,20-triketo-9a,16B-dibromo-17a-hydroxy- 21-acetyloxy-A -pregnene.The 21-acyl derivative of the natural modification of3,11,20-triketo-17a,21dihydroxy- A -pregnene according to infraredspectrum, melting point and optical rotation is identical with thecorresponding acyl derivative of natural cortisone. Thusly, it is to beunderstood that the optically active isomers referred to hereinbefore asthe natural modification are those which through the course of reactionsas afore schematically outlined starting with the dextro-rotatory formof 3-keto-17-formyl-A -androstatriene provide for the acyl derivativesof natural cortisone.

While as aforedescn'bed the 16-halo-17-hydroxy-17- (acyloxyacetyl)cyclopentano 10,13 dimethyl-A decahydrophenanthren 3 one compound(Compound VII) was employed to prepare the 9-halo-11-hydroxy additionproduct (Compound VIII) it has been found that it (i. e. Compound VII)upon dehalogenating provides for al7-hydroxy-17-(acyloxyacetyl)-cyclopentano- 10,13 dimethyl A4301)decahydrophenanthren-3-one which compound upon reacting with ahypohalous acid produces a 9-halo-ll-hydroxy addition product whichaddition product upon dehalogenating yields a 11,17-

dihydroxy 17 (acyloxyacetyl)-cyclopentano-10,13-dimethyl Adodecahydrophenanthren-3-one. This sequence of steps is outlinedschematically as follows, R and as having the same significance asaforedescribed.

As illustrative these steps proceeding from Compound VII to CompoundsXII and XIII and finally to Compound XIV is the following:

Example X To a suitable reaction vessel containing 10 parts by weight ofRaney nickel, approximately 100 parts by weight of acetone and about 10parts by weight of water is added and intimately mixed 3 parts by weightof d!- 3,20 diketo 16B bromo 17a hydroxy-Zl-acetyloxy- A -pregnadieneand the mixture so obtained refluxed in an atmosphere of nitrogen forabout 4 hours. The reaction mix is then filtered and the residue washedwith warm acetone. The washings and original filtrate are combined andsubjected to vacuum distillation. The residue is then taken up withchloroform and the solution so formed washed with water and dried. Thedried solution is then subjected to vacuum distillation whereupon thereis obtained white crystalline dl-3,20-diketo- 17a-hydroxy-2l-acetyloxy-A-pregnadiene.

Similarly the individual optically active isomers such as the naturalmodification of 3,20-diketo-17u-hydroxy- 2l-acetyloxy-A -pregnadiene areobtained beginning with the appropriate optically active isomer of3,20-diketo 16B bromo 17cc hydroxy 21 acetyloxy- A -pregnadiene. Thenatural modification or dextro-rotatory from of3,20-diketo-l7ot-hydroxy-2l-acetyloxy-A -pregnadiene possesses a meltingpoint of 233-236 C.

The aforedescribed dl-3,20-diketo-17u-hydroXy-2l-acetyloxy-A-pregnadiene upon reacting with a hypohalous acid such as hypobromousacid in accordance with the process of Example VII produces whitecrystalline dl 3,20 diketo 9a bromo 115,17a dihydroxy -21- acetyloxy-A-pregnene which 9-bromo-11-hydroxy addition product upon dehalogenatingusing Raney nickel provides fordl-3,20-diketo-1113,17u-dihydroxy-21-acetyloxy-A -pregnene whichcompound has the same infrared spectrum as the (21-) acetate of17-hydroxy corticosterone. Similarly but beginning with the.naturalmodification of 3,20-diketo-17a-hydroxy-2l-acetyloxy-A pregnadiene theacetate obtained is identical with the (21-) acetate of 17-hydroxycorticosterone.

The natural modification of 3-keto-16,17-oxido-17- formyl-A-androstadiene referred to in column 31, line 65, is a white crystallinesubstance melting at 193- 197" C. The natural modification of3-keto-16,17-oxido- 17-carboxy-A -androstadiene referred to in column 4,line 39, is a white crystalline substance melting at 211-2l2 C. Thenatural modification of 3,20-diketo- 16,17-oxido-21-diazo-A -pregnadienereferred to in column 5, line 25, is a yellow crystalline substancemelting at -168 C. The natural modification of 3,20- diketo 16 3 bromo17a-hydroxy-21-acetyloxy-A pregnadiene referred to in column 6, line 25,is a White crystalline substance melting at 146148 C.

This application is a division of co-pending application Serial No.369,944, filed July 23, 1953, now U. S. Patent No. 2,759,929.

While this invention has been described with respect to certainembodiments it is not so limited and it is to be understood thatvariations and modifications thereof obvious to those skilled in the artmay be made without departing from the spirit or scope of thisinvention.

What is claimed is:

16,17 oxido-17-(diazoacetyl)-cyclopentano-10,13-dimethyl-A-decahydrophenanthrene-3-one No references cited.

